Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.
Department of Food and Nutrition, Sunchon National University, Sunchon, 57922, Republic of Korea.
Cell Mol Life Sci. 2023 Mar 16;80(4):91. doi: 10.1007/s00018-023-04752-5.
Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 trafficking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A when inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and its effects on endothelial permeability is largely unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates endothelial permeability. Phosphorylated VEGFR2 at the cell-cell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle. Inhibition of the function of KIF13B attenuated phosphorylation of VEGFR2 at Y951, SRC at Y416, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 trafficking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of the blinding eye disease wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 trafficking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, which suggests a promising strategy for mitigating vascular leakage associated with inflammatory diseases.
过量的血管内皮生长因子-A（VEGF-A）信号会导致疾病中的血管渗漏和血管生成。VEGFR2 通过驱动蛋白-3 家族蛋白 KIF13B 向细胞表面转运，对于响应 VEGF-A 诱导血管生成至关重要。然而，KIF13B 如何调节 VEGF 诱导的信号以及对内皮通透性的影响的精确机制在很大程度上尚不清楚。在这里，我们表明，通过 Rab11 阳性回收小泡介导的内化 VEGFR2 的 KIF13B 再循环调节内皮通透性。细胞-细胞连接处的磷酸化 VEGFR2 在内化时与 Rab5 阳性早期内体中的 KIF13B 相关联。KIF13B 通过 Rab11 阳性回收小泡介导 VEGFR2 的再循环。抑制 KIF13B 的功能会减弱 VEGFR2 在 Y951、SRC 在 Y416 和 VE-钙粘蛋白在 Y685 的磷酸化，这对于内皮通透性是必需的。VEGFR2 向细胞表面的转运失败导致溶酶体中 VEGFR2 的积累和降解。此外，在致盲眼病湿性年龄相关性黄斑变性（AMD）的动物模型中，抑制 KIF13B 介导的 VEGFR2 转运也减轻了血管渗漏。因此，这些结果确定了 VEGFR2 再循环到细胞表面在介导血管通透性中的基本作用，这提示了一种有前途的策略，可以减轻与炎症性疾病相关的血管渗漏。
